A green journey to the making of magic bullets

Document Type

Conference Proceeding

Publication Date

2018

Keywords

Antibiotics; Bioprocess technology; Environmental sustainability; Yeast cell surface enzymes

Abstract

Semi-synthetic cephalosporins, constituting the largest portion in the worldwide sales of beta-lactam antibiotics, have been used extensively for decades as “magic bullets” to combat microbial infections. The global cephalosporin market was valued at US$78,000 million in 2016 and it is estimated to increase by 14% by 2023. Most of the marketed cephalosporins are semi-synthetic. However, the methodologies involved are environmentally-damaging because toxic chemicals are used. The increasing annual demand of semi-synthetic cephalosporins and the concept of environmental sustainability pose a dire need to develop alternative approaches for “greener” production of antibiotics. Microorganisms have been heralded as a solution to many of the contemporary world’s most pressing issues. One of the frontiers in microbial biotechnology is to help solve environmental and sustainable resources problems, and scientists have been working vigorously to harness single-celled systems to produce high value fine chemicals such as commodity chemicals, therapeutic intermediates, and essential nutrients. Bioprocess technology has operational advantages: the procedures are low cost, high yield, and environmentally-sustainable. My research laboratory has been working on developing a sustainable and effective bioprocess using enzymes for the biosynthesis of 7-aminocephalosporanic acid (7-ACA), a cephem nucleus for the production of nearly two-thirds of the global commercial semi-synthetic cephalosporins. In particular, using bioinformatics and modeling, we have characterised a variant D-amino acid oxidase (DAAO) with enhanced catalytic properties suitable for industrial applications. By using variant DAAO and glutaryl-7-aminocephalosporanic acid acylase (GL-7-ACA acylase), we have patented a two-enzyme biosystems for direct biosynthesis of 7-ACA with overall conversion rate approaching 100%. Immobilised enzymes are more robust and exhibit enhanced resistance to industrial and environmental challenges. However, immobilised enzymes are expensive and preparation involves tedious multi-step schemes. Yeast surface display technology represents a tangible and sustainable alternative approach to immobilised enzymes with industrial relevance. Enzyme biocatalysts are displayed on cell surface where a direct enzyme-substrate interaction is facilitated with higher stability and catalytic activity. The new paradigm in pharmaceutical industry is the development of multi-enzyme sequential reactions in one-pot to minimise enzyme inhibition and formation of by-products. We would like to address the problems and develop a streamlined bioprocess relevant to the concept of environmental sustainability by constructing a functional assembly of DAAO and GL-7-ACA acylase for one-pot production of 7-ACA. We reckon that yeast display technology is particularly suitable for biosynthesis of 7-ACA via an establishment of a functional assembly of enzymes with close proximity. Here, I would like to report the latest findings of my research on this area and the potential industrial applications.

Source Publication

International Conference on Applied Education, Technology and Innovation (AETI), on 16-18 April 2019, at the Technological and Higher Education Institute of Hong Kong (THEi)

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